Fatigue and cognition - hormonal perspectives

Fatigue is a common complaint and considered a very challenging symptom to cope with in many different medical diseases. The assessment of fatigue is bound up with the problems of both conceptualization and definition. In addition, few studies have investigated suitable neuropsychological tests to examine fatigue and its consequences. This thesis evaluates whether neuropsychological tests can elicit cognitive fatigue. It also investigates whether specific hormones and hormone replacement therapy influence fatigue as well as cognitive performance. Study I examined and compared neuropsychological measures of cognitive fatigue with self-rated fatigue in patients with mild traumatic brain injury (mTBI). These patients scored significantly higher than controls on both self-rated and on test-derived measures of cognitive fatigue. Cognitive fatigue was best captured with a score derived from the WAIS Digit Symbol. From our findings we concluded that cognitive fatigue was independent of depression and sleep disorder. Self-rated fatigue, on the other hand, was highly correlated to depression. Study II compared the effect of combined testosterone and estrogen replacement with estrogen treatment alone on subjective and objective measures of memory in oophorectomized women. Treatment with testosterone undecanoate 40 mg and estradiol 2 mg was associated with lower performance on immediate verbal memory compared to treatment with estrogen plus placebo. All other memory functions were unaffected. Study III explored cognitive fatigue in oophorectomized women, and whether hormonal treatment regimens, as described in study II, were related to self perceived well-being, estrogen or testosterone serum levels. We found that cognitive fatigue was frequent in oophorectomized women and negatively associated to self-perceived health and positively associated to BMI. However, treatment with testosterone + estrogen or estrogen alone had no significant effect on cognitive fatigue. Study IV investigated fatigue and cognitive performance in patients with Graves’ disease (GD). As compared to controls, patients with GD scored significantly higher on self-rated fatigue and had a higher frequency on the cognitive fatigue. They also demonstrated lower performance on learning, memory, and various tests of executive functioning. Depression was associated with self-rated fatigue but not with the cognitive fatigue measure. High-free triiodothyronine (T3) levels were positively associated to better cognitive functions but negatively to self-rated everyday consequences of fatigue among the patients. In conclusion: Cognitive fatigue measure, derived from Digit Symbol, could be a useful instrument to capture fatigue. It enables us to calculate an index of cognitive fatigue where neither depression nor sleep disturbance interfere with the result. Cognitive fatigue seems to be related to BMI and self-rated health but not directly related to hormonal levels. A curvilinear relation to sex hormones and the estrogen/testosterone ratio seem more likely. Indirect hormonal imbalances could influence subtle neuronal mechanisms leading to discrete neuropsychological dysfunctions

A CLINICALLY RELEVANT CLOSED-HEAD MODEL OF SINGLE AND REPEAT CONCUSSIVE INJURIES IN THE ADULT RAT USING A CONTROLLED CORTICAL IMPACT DEVICE

Recently, cases of multiple concussions, or mild traumatic brain injury, in athletes have received increased attention. Compared to single concussion (sTBI), repeat concussions (rTBI) can produce significant long-term consequences and increased risk for neurodegenerative disease. However, mechanisms underlying this difference are poorly understood and are best elucidated using an animal model. Closed-head models of rTBI have been developed in mice and juvenile rats, but few have been developed in the adult rat. To the best of our knowledge, there is no closed-head model using a commercially available device, including the Controlled Cortical Impact (CCI) device. We developed a clinically relevant closed-head injury model of concussion in the adult rat using a Leica CCI device. Rats were placed in a stereotax frame without ear-bars, on a foam-bed base. The head was stabilized against a Plexiglas frame to control impact while allowing head movement. A 6.5 m/s impact was delivered onto the head surface over the sensorimotor-cortex at a depth of 10.0 mm from the skin. rTBI animals received 3 injuries, 48 hours apart. A subset of sTBI animals received two subsequent exposures to anesthesia (sTBIac), 48 hours apart, to mimic the extra exposure experienced by the rTBI animals. We initially created a model of sTBI before continuing to examine rTBI. Sham and sTBI rats were initially assessed at days 1-3 post injury using tests of memory (Novel Object Recognition), forelimb coordination (foot fault) and activity/anxiety (open field). Blood corticosterone levels were measured pre-injury and pre-sacrifice (day 4). At this time point, sTBI animals showed memory deficits without locomotor deficits or an anxiety response. The study was then expanded by adding rTBI animals and sTBI/sTBIac animals sacrificed 8 days after the initial injury. Rats were assessed at days 5-7 after the initial injury. Results indicate that both sTBI and rTBI animals show deficits in coordination and hypo-locomotion at day 5. Although sTBI rats showed no anxiety response rTBI rats did show anxiety (spent less time in the center of an open field). sTBI rats displayed memory deficits 3 days post-injury, but not day 7. rTBI rats continued to show memory deficits at day 7. Both had higher resting corticosterone levels post-injury compared to both their baseline levels and to sham and day 4 sTBI animals. No obvious gross pathology was observed on the cortical surface or in coronal sections. Our data presents a model of closed-head CCI in an adult rat that results in clinically relevant markers of concussion and an early delineation between single and repeat concussions

Chronic traumatic encephalopathy and the locus coeruleus

Chronic Traumatic Encephalopathy (CTE) is a neurodegenerative disease that is associated with repetitive traumatic brain injury like those sustained in sport, military combat, and other activities with repetitive head impact exposure. Repetitive head impacts typically cause mild traumatic brain injury (mTBI) resulting in both concussive and subconcussive injury. Repeated mTBIs injuries appear to cause an abnormal accumulation of proteins, including hyperphosphorylated tau (p-tau) and TDP-43, progressive axonal failure with gradual structural degradation, microvascular disruption, breach of blood-brain barrier, neuroinflammation and microglial activation; each of these manifestations lead to axonal degeneration and neuronal death, which impairs neuronal pathways and are likely to give rise to CTE symptoms. CTE can be microscopically characterized mainly by p-tau accumulation in perivascular spaces and at the depths of the cortical sulci. Clinical presentation of CTE may include behavioral, mood, cognitive, or motor symptoms. Some of the common symptoms include impulsivity, aggression, anxiety, depression, memory impairment, dementia, and suicidality. The Locus Coeruleus (LC), a nucleus in the pons of the brainstem, is suspected to be involved in CTE. The LC provides the main source of norepinephrine to the entire brain and is critical for its control over arousal, behaviors, attention, and memory. Dysfunction of the locus coeruleus has shown to cause a wide array of symptoms, many of which are similar to those seen in CTE. Furthermore, the LC is affected in many other neurodegenerative diseases and is believed to be responsible for the progressive and widespread nature of the various diseases and their clinical symptoms. Although the LC has been implicated in CTE there have been no studies examining LC pathology in relation to the disease progression or its symptoms. We hypothesize LC CTE pathology should increase with the severity of CTE. Furthermore, increased CTE pathology in the LC should create disturbances to the LC and the LC-NE system and manifest clinically. Specifically, LC CTE pathology may be associated with age of onset of general behavioral and cognitive symptoms as well as individual symptoms and outcomes including impulsivity, depression, depressed mood and death by suicide. To determine this, a postmortem study was performed on 184 individuals with a history of RHI and no comorbid diseases examining the relationship between AT8-immunopositive tau density in the LC and various clinical variables. The study found that LC AT8 density showed a significant positive correlation with duration of repetitive head impact (RHI) exposure when controlled for age. There also was a significant increase in LC AT8-immunoreactive tau in cases with stage III and IV CTE compared to those with no CTE and stage I and II CTE, and AT8 density was predictive of CTE stage when controlled for age. There were no significant relationships found between density of LC AT8-immunoreactive tau and age of any CTE symptom onset or individual symptom (impulsivity, depressed mood, MDD, death by suicide) presence. Future studies should continue to evaluate CTE pathology in the LC and its effects on both the pathological and clinical characteristics of the disease

Efeitos do pré e do pós-condicionamento com N-metil-D-aspartato sobre o comportamento e a viabilidade celular em camundongos expostos ao traumatismo crânio-encefálico

Tese de Doutorado apresentada ao Programa de Pós-Graduação em Ciências da Saúde da Universidade do Extremo Sul Catarinense para obtenção do título de Doutor a em Ciências da Saúde.Estudos mostram um importante papel do N-metil-D-aspartato (NMDA) em lesão cerebral. O presente estudo teve como objetivo verificar parâmetros de memória, ansiedade, depressão e viabilidade celular em cérebro de camundongos pré ou pós-condicionados com NMDA e expostos ao modelo animal de traumatismo crânio-encefálico (TCE) leve. Os camundongos albino CF-1 machos foram pré tratados com NMDA (75 mg/kg) 24 h antes ou, 15 min ou 1 h após o TCE. Após 24 horas do TCE os camundongos foram submetidos a testes comportamentais de memória, ansiedade e depressão. Os testes de memória foram realizados 1,5 h e 24 h e 7 dias após o tratamento. A viabilidade celular foi avaliada no córtex cerebral e hipocampo 96 h após o trauma. No teste de habituação, todos os animais aprenderam a tarefa. No teste da esquiva inibitória, apenas os camundongos pré tratados com NMDA mostraram comprometimento da memória de longo prazo (7 dias após a sessão de treino). No teste de reconhecimento de objetos, camundongos tratados com NMDA foram protegidos contra os déficits causados pelo TCE, em ambos os regimes de tratamento com NMDA. Após o TCE não foi observado comportamento do tipo depressivo ou ansioso. Foi observado diminuição da viabilidade celular no hipocampo após o TCE, porém o pré e o pós-condicionamento com NMDA foram eficazes em aumentar a viabilidade celular. Em conclusão, tanto o pré quanto o pós-condicionamento com NMDA protegeu os déficits na memória e aumentou a viabilidade celular no hipocampo de camundongos expostos ao TCE.Recently, studies have appointed for a role of N-methyl-D-aspartate (NMDA) in the brain injury. This study aimed to verify memory, anxiety/depression parameters and cellular viability in the brain of mice pre and postconditioned with NMDA and subjected to the model of mild traumatic brain injury. Male albino CF-1 mice were pre-treated with NMDA (75 mg/kg) and subjected to brain trauma, and then 24 h after mice were submitted to memory tasks, anxiety and depression-like behavioral tests. The memory tests were evaluated at 1.5h and 24 h and 7 days after the training. The cellular viability was evaluated in the cerebral cortex and hippocampus 96h after trauma. In another part, it was evaluate the effects of postconditioned with NMDA (75 mg/kg) on habituation and novel object recognition. The cellular viability was assessed 96h after TBI. In the habituation test, all mice learn the task. In the step-down inhibitory avoidance test, only the mice treated only with NMDA shown impairment long-term memory (7 days after training session). In the object recognition task mice preconditioned with NMDA were protected against impairment induced by TBI in both short and long-term memory. The evaluation of anxiety/depression behavior showed any changes after TBI. In the hippocampus of the mice subjected to trauma the cellular viability was reduced and both pre and postconditioning with NMDA was able to protect this damage. In conclusion, NMDA pre and postconditioning induced impairment of long-term memory, but it was able to protect to the novel recognition memory impairment and increase the cellular survival in hippocampus of mice exposed to traumatic brain injury

Impaired Prefrontal Hemodynamic Maturation in Autism and Unaffected Siblings

BACKGROUND: Dysfunctions of the prefrontal cortex have been previously reported in individuals with autism spectrum disorders (ASD). Previous studies reported that first-degree relatives of individuals with ASD show atypical brain activity during tasks associated with social function. However, developmental changes in prefrontal dysfunction in ASD and genetic influences on the phenomena remain unclear. In the present study, we investigated the change in hemoglobin concentration in the prefrontal cortex as measured with near-infrared spectroscopy, in children and adults with ASD during the letter fluency test. Moreover, to clarify the genetic influences on developmental changes in the prefrontal dysfunction in ASD, unaffected siblings of the ASD participants were also assessed. METHODOLOGY/PRINCIPAL FINDINGS: Study participants included 27 individuals with high-functioning ASD, age- and IQ-matched 24 healthy non-affected siblings, and 27 unrelated healthy controls aged 5 to 39 years. The relative concentration of hemoglobin ([Hb]) in the prefrontal cortex was measured during the letter fluency task. For children, neither the [oxy-Hb] change during the task nor task performances differed significantly among three groups. For adults, the [oxy-Hb] increases during the task were significantly smaller in the bilateral prefrontal cortex in ASD than those in control subjects, although task performances were similar. In the adult siblings the [oxy-Hb] change was intermediate between those in controls and ASDs. CONCLUSION/SIGNIFICANCE: Although indirectly due to a cross-sectional design, the results of this study indicate altered age-related change of prefrontal activity during executive processing in ASD. This is a first near-infrared spectroscopy study that implies alteration in the age-related changes of prefrontal activity in ASD and genetic influences on the phenomena

The Heart Is at Risk: Understanding Stroke-Heart-Brain Interactions with Focus on Neurogenic Stress Cardiomyopathy-A Review.

In recent years, it has been convincingly demonstrated that acute brain injury may cause severe cardiac complications-such as neurogenic stress cardiomyopathy (NSC), a specific form of takotsubo cardiomyopathy. The pathophysiology of these brain-heart interactions is complex and involves sympathetic hyperactivity, activation of the hypothalamic-pituitary-adrenal axis, as well as immune and inflammatory pathways. There have been great strides in our understanding of the axis from the brain to the heart in patients with isolated acute brain injury and more specifically in patients with stroke. On the other hand, in patients with NSC, research has mainly focused on hemodynamic dysfunction due to arrhythmias, regional wall motion abnormality, or left ventricular hypokinesia that leads to impaired cerebral perfusion pressure. Comparatively little is known about the underlying secondary and delayed cerebral complications. The aim of the present review is to describe the stroke-heart-brain axis and highlight the main pathophysiological mechanisms leading to secondary and delayed cerebral injury in patients with concurrent hemorrhagic or ischemic stroke and NSC as well as to identify further areas of research that could potentially improve outcomes in this specific patient population

Long-term functional outcomes and correlation with regional brain connectivity by MRI diffusion tractography metrics in a near-term rabbit model of intrauterine growth restriction

Background: Intrauterine growth restriction (IUGR) affects 5-10% of all newborns and is associated with increased risk of memory, attention and anxiety problems in late childhood and adolescence. The neurostructural correlates of long-term abnormal neurodevelopment associated with IUGR are unknown. Thus, the aim of this study was to provide a comprehensive description of the long-term functional and neurostructural correlates of abnormal neurodevelopment associated with IUGR in a near-term rabbit model (delivered at 30 days of gestation) and evaluate the development of quantitative imaging biomarkers of abnormal neurodevelopment based on diffusion magnetic resonance imaging (MRI) parameters and connectivity. Methodology: At +70 postnatal days, 10 cases and 11 controls were functionally evaluated with the Open Field Behavioral Test which evaluates anxiety and attention and the Object Recognition Task that evaluates short-term memory and attention. Subsequently, brains were collected, fixed and a high resolution MRI was performed. Differences in diffusion parameters were analyzed by means of voxel-based and connectivity analysis measuring the number of fibers reconstructed within anxiety, attention and short-term memory networks over the total fibers. Principal Findings: The results of the neurobehavioral and cognitive assessment showed a significant higher degree of anxiety, attention and memory problems in cases compared to controls in most of the variables explored. Voxel-based analysis (VBA) revealed significant differences between groups in multiple brain regions mainly in grey matter structures, whereas connectivity analysis demonstrated lower ratios of fibers within the networks in cases, reaching the statistical significance only in the left hemisphere for both networks. Finally, VBA and connectivity results were also correlated with functional outcome. Conclusions: The rabbit model used reproduced long-term functional impairments and their neurostructural correlates of abnormal neurodevelopment associated with IUGR. The description of the pattern of microstructural changes underlying functional defects may help to develop biomarkers based in diffusion MRI and connectivity analysis